The high rate of cancer morbidity and mortality remains a major concern among the population in Western societies. In addition to having an impact on the cancer patients and members of their immediate families, cancer inflicts a large burden on society. The cost of cancer treatment and patient care is typically high and contributes to increased cost of health insurance and results, in turn, in a higher percentage of uninsured people and, consequently, in an increased economic burden when uninsured people become sick or injured. Cancer also causes a significant negative impact on businesses due to prolonged absences of cancer patients from work.
Although methods of cancer treatment have greatly improved over the years, many challenges, most notably relapse among cancer patients and difficulties in treating patients in advanced stages of cancer as well as with metastatic diseases or with systemic cancers such as leukemia or lymphoma, remain. For example, improved diagnostic methods combined with better surgical techniques allow oncologists to remove tumor with greater confidence, while at the same time minimizing the removal of normal tissue. As such, the recovery time for patients can be decreased and psychological impact is reduced. However, surgery is only one of the few useful tools for treating patients with localized, non-metastatic tumors or the tumors which are minimally spread.
Chemotherapy is another treatment of choice for certain types of cancers. However, chemotherapeutic methods are generally not specific for tumor cells as compared to normal cells. As a result, chemotherapy is generally associated with serious side effects and can be particularly devastating to the patient's immune system and to rapidly dividing tissues, such as tissues in liver, kidneys, gut, and epithelium.
Cancer progression is dependent on angiogenesis, or the sprouting of new blood vessels that penetrate every solid tumor. The rapid tissue proliferation which defines cancer results in a number of adaptive cellular responses, primary among which are the distinct but related processes of angiogenesis and increased glycolysis. Angiogenesis is primarily driven by several mitogenic factors such as vascular endothelial growth factor (VEGF) and its receptors play a key role. While neovascularization is essential in embryonic development, it is highly undesirable in cancers because these nascent vessels infuse tumor tissue and provide them with increased oxygenation and nutrient content for more rapid growth. Angiogenesis is particularly pernicious because it poses a double threat: not only it accelerates tumor growth, but also provides a gateway to metastasis via the newly formed vasculature. As it is metastatic growth which exerts the greatest impact on overall patient survival, angiogenesis represents a critical chemotherapeutic target. Moreover, vascular targets should not engender resistance to therapy because they are not subject to the multiple mutations which occur in malignant cells. One of the primary advantages of targeting the blood supply (vasculature) is that, unlike cells in the cancerous tissues, the cells that comprise blood vessels are genetically stable and, therefore, should have diminished resistance to therapy.
As tumor cells continue to proliferate, they are forced farther away from the blood supply carrying needed oxygen and nutrients for metabolic processes and therefore cannot attain adequate oxygen perfusion. The ensuing hypoxia1 results in a switch to an anaerobic metabolism which selects for cells with upregulated glycolysis.2 Enhanced glycolytic function then leads to increased generation of lactic acid which lowers intracellular pH and can facilitate the degradation of the extracellular matrix and basement membrane, thereby promoting angiogenesis.3 Glycolysis confers a significant advantage in overcoming growth restraints during tumorigenesis4,5 and most primary metastatic tumors demonstrate significant upregulation of glycolytic enzymes like hexokinases 1 and 2 and glucose transporters GLUT1 and GLUT3.6 
Hypoxia is one of the most important hallmarks of solid tumors that plays a vital role in cell proliferation, signaling and growth.7 A typical neoplasm is usually devoid of blood vessels in its early stage. The rapidly proliferating cells contribute to development of hypoxia.8 Despite the fact that cell proliferation decreases in those parts of a tumor that are away from blood vessels,9 they tend to select for more aggressive cellular phenotypes. Moreover, it has been reported that the hypoxic tissue away from the blood vessels give rise to cells that have lost sensitivity to p53-mediated apoptosis.7 
Hypoxia also leads to upregulation of genes involved in drug resistance, such as P-glycoproteins10,11 in addition to the fact that lack of adequate blood supply to hypoxic cells severely impairs the delivery of drug to these cells.12,13 Most importantly, from a transcriptional standpoint, hypoxia results in an upregulation of genes involved in angiogenesis14 and tumor invasion15 resulting in more aggressive cancer phenotype.16 
In cells and tissues, response to hypoxia is primarily mediated by the family of hypoxia-inducible transcription factors, among which hypoxia-inducible factor 1 (HIF1) plays a major role. It is a heterodimeric transcription factor which mediates regulation of many key genes upregulated in a hypoxic state (FIG. 1a).17 During normoxic conditions, the a-subunit of HIF1 is regulated by hydroxylation at proline residues 402 and 564;18 these modifications serve as a docking site for the von Hippel-Lindau (pVHL) protein19 to bind HIF1 and tag it with ubiquitin for subsequent proteasomal degradation.20 However, under hypoxic conditions, HIF1α accumulates, enters the nucleus and dimerizes with its beta subunit, aryl hydrocarbon receptor nuclear translocator (ARNT, or HIF1β),21 It binds to the promoter region of hypoxia inducible genes possessing hypoxia-response elements (HREs),22 including VEGF, c-Met, EPO, and GLUT-1.23,24 Because low oxygen levels also preclude hydroxylation of another regulatory site at Asn803,25-30 the coactivator CREB binding protein (CBP)/p30031-33 is recruited via binding the C-terminal domain of HIF1α and promotes elevated expression levels of hypoxia-inducible genes (FIG. 1b).34-36 In many tumor cells where oncogenic mutations in RAS, SRC and HER2/NEU/ERBB2 are found, high levels of HIF1α have been detected even under well-oxygenated condition.37 
It has been shown that antisense construct of HIF1α eradicates in vivo a small transplanted thymic lymphoma and even increases the efficacy of immunotherapy against larger tumors.38 Small molecule inhibitors of microtubules, such as 2-methoxyestradiol, vincristine and paclitaxel have been shown to reduce HIF1α levels in vitro and also reduce tumor growth and vascularization.39 However, it is not clearly understood whether the effects shown in tumor growth reduction is due to microtubule inhibition or reduction of HIF1α levels.
HIF1 interacts primarily with the CH1 domain of CBP/300 through a series of key cysteine residues and this interaction is driven by hydrophobic forces. It was shown that the natural product chetomin (FIG. 2, vide infra), a fungal metabolite of the Chaetomium sp., demonstrated potent and specific inhibition of the HIF/p300 complex. Because p300/CBP is absolutely required for HIF1-mediated transactivation, blocking the association of HIF1 and p300/CBP effectively downregulates transcription.